Targeted delivery of Lu-177 to tumor vasculature

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$1,791,385.00
Award Year:
2011
Program:
SBIR
Phase:
Phase II
Contract:
2R44CA141806-02A1
Award Id:
n/a
Agency Tracking Number:
R44CA141806
Solicitation Year:
2011
Solicitation Topic Code:
NCI
Solicitation Number:
PA10-050
Small Business Information
115A Commerce Drive, Brookfield, CT, 06804-
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
966566465
Principal Investigator:
JOSEPH BACKER
(203) 775-5677
jbacker@sibtech.com
Business Contact:
JOSEPH BACKER
(203) 775-5677
jbacker@sibtech.com
Research Institute:
Stub




Abstract
DESCRIPTION (provided by applicant): Currently available anti-angiogenic drugs inhibit VEGF/VEGFR signaling, which leads to transient vascular regression followed by rebound of drug-resistant vasculature, which significantly decrease the therapeutic efficacy of very expensive anti-angiogenic treatment. To overcome this problem, we are developing a cytotoxic 177Lu radiopharmaceutical, scVEGF/Lu. This radiopharmaceutical is based on engineered single-chain VEGF (scVEGF) and it accumulates in tumor endothelialcells via endocytosis mediated by overexpressed VEGFR-2. In Phase I we optimized the composition of scVEGF/Lu, assessed its radiotoxicity and dosimetry and performed initial therapeutic efficacy and mechanistic studies in orthotopic breast tumor models. Our results demonstrate that a single injection of a safe dose of scVEGF/Lu induces destruction of tumor vasculature sustainable for at least 30-35 days and a widespread apoptosis in tumor without significant overall radiotoxicity. In contrast, FDA-approvedsunitinib and bevacizumab failed to induce sustainable destruction of tumor vasculature, suggesting potential advantages of scVEGF/Lu. In Phase II we will focus on late pre-clinical development of scVEGF/Lu as a novel component of anti- angiogenic therapy, using orthotopic mouse models of recurrent breast cancer, including a model of human triple negative breast cancer. First, we will establish the dose- and time-dependences for scVEGF/Lu-induced destruction of tumor vasculature and potential roles of overexpressed endogenous VEGF and immunocompetent environment in therapeutic efficacy of scVEGF/Lu. Next, we will establish optimal sequence for scVEGF/Lu-doxorubicin combination as adjuvant therapy for recurrent breast cancer. Considering that scVEGF is a physiologically active protein, we will also establish the safety profile for scVEGF-PEG-DOTA conjugate. We expect that by the end of Phase II of the project we will have evidence-based indications for safe use of scVEGF/Lu in adjuvant anti-angiogenic therapy for breast cancer. We will also have a GLP-grade for dosimetry studies. This data will be used for filing IND or eIND with FDA for Phase I clinical trials with scVEGF/Lu in breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer, and eventually will be explored for treatment of other cancers. PUBLIC HEALTH RELEVANCE: To increase the efficacy anti-angiogenic therapy, it is necessary to sustain tumor vascular regression and to inhibit vascular rebound. For this, we develop a novel 177Lu radiopharmaceutical, scVEGF/Lu, which delivers lethal doses of 177Lu in tumor endothelial cells. In orthotopic models of breast cancer, scVEGF/Lu induces destruction of tumor vasculature and widespread apoptosis in tumor, without significant overall radiotoxicity. In this project we will evaluate the potential of scVEGF/Lu as a novel component of anti-angiogenic therapy that could make a significant impact on outcome of triple negative breast cancer. We expect that this study will provide evidence-based indications for safe use of scVEGF/Lu as a mono- or combination therapy as adjuvant therapy for breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer and eventually will be explored for treatment of other cancers.

* information listed above is at the time of submission.

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